1. Technical Field
The present disclosure relates to oligopeptides having improved osteoblastic differentiation ability, and more particularly, to oligopeptides used for enhancing osteointegration and osteogenesis in dental implants.
2. Description of the Related Art
Optimal use of dental implants requires short induction periods of osteointegration. That is, if osteointegration is not successively achieved within a short period of time, the treatment period becomes longer and the success rate of an implant surgery is declined due to the fail of initial osteointegration. Accordingly, there is an absolute need to enhance osteointegration and osteogenesis abilities.
For this, it has been developed a method of directly coating a growth factor such as TGF-β (transforming growth factor-β), IGF-1 (Insulin-like growth factor-1) and the like or a physiologically active substance such as BMP (bone morphogenetic protein) for promoting the proliferation and differentiation of osteoblasts on the surface of an implant, or spreading the factor or substance around the detect site during implant procedures. However, the coating of the physiologically active substance on the surface of an implant before the implant surgery causes several problems in that such an active substance is required in a large amount and unable to effectively remain at the implanted site, and thus, its application range is very restrictive. Further, the coating of the active substance is conducted at extremely limited area, and thus, it is impossible to achieve effective osteanagenesis and osteointegration over the whole surface of an implant, and implant surgery costs increase. In addition, such an implant surgery is not yet standardized and is inefficient for the management of patient, thereby being difficult to be adopted as a standardized method of an implant surgery.
BMPs interact with BMP receptors (BMPRs) on the cell surface to initiate intracellular signal transduction and play an important role in formation of alveolar bone. BMP receptors belong to a TGF-β transmembrane serine-threonine kinase receptor family. Efficient intracellular signal transduction through ligand binding is achieved by the following the steps of: forming a heteromeric receptor complex between a type I receptor and a type II receptor, inducing cross-phosphorylation from the type II receptor to the type I receptor, activating the Smad signaling cascade, and then, expressing a target protein. The BMP receptor includes three kinds of the type I receptors (ActR-I, BMPR-IA, BMPR-IB) and three kinds of the type II receptors (ActR-II, ActR-IIB, BMPR-II). It has been reported that all BMPs of the TGF-β superfamily interact with BMPR-II which is bound to BMPR-IA or BMPR-IB, and ActR-II, ActR-IIB and ActR-I do not interact with BMP-4. These facts suggest that BMPR-IA or BMPR-IB and BMPR-II are BMP-specific receptors. Therefore, the development of oligonucleotide sequences having higher binding affinity to a BMP-specific receptor present on the cell surface can further efficiently induce osteoblastic differentiation.
Meanwhile, there are several patent documents in relation to the development of BMP-derived peptides for stimulating the differentiation and proliferation of osteoblasts and the introduction of the BMP-derived peptides into the surface of an implant.
Korean Patent Publication No. 2006-0110189 entitled “Synthetic peptides for treatment of dental implant surfaces” discloses oligopeptides represented by the formula R1-(A-B-C)n-R2-(A-B-C)m-L (wherein, R1 is H, an amino acid residue, a fatty acid residue or a biodegradable polymer main chain, R2 is a spacer, and L is a linker). Said oligopeptides can promote bone growth and shorten the induction period of osteointegration by being directly treated on the surface of a dental implant.
Korean Patent Publication No. 2006-0101019 (Patent No. 0676945) entitled “Bone graft and scaffolding materials immobilized with osteogenesis enhancing peptides on the surface” relates to bone graft and scaffolding materials whose surface is coated with a cell adhesion-inducing peptide and/or a tissue growth factor-derived peptide. In particular, it discloses osteogenesis protein (BMP-2, 4, 6)-derived peptides.
Korean Patent Publication No. 2006-0082060 (Patent No. 0630903) entitled “Membrane and implant immobilized osteogenic enhancing peptides on the surface” relates to a membrane and an implant in which a cell adhesion-inducing peptide or a tissue growth factor-derived peptide is coated on a crosslinker-bound surface. It discloses osteogenesis protein (BMP-2)-derived peptides.
However, the oligopeptides disclosed in said patent documents still fail dramatically to shorten the induction period of initial osteointegration.
Further, Korean Patent Application No. 2008-0054730 discloses oligopeptides having a specific sequence (as a key peptide, R1-CKIPKPSSAPTELSAISMLYL-R2 (SEQ ID NO: 8), referred to as ‘PEP111’) which shorten the induction period of initial osteointegration and promote osteogenesis (all of the patents referred to herein are hereby incorporated by reference in their entirety).
However, the oligopeptides disclosed in said patent application show very low binding affinity to a BMP-specific receptor, and thus, their osteointegration and osteogenesis abilities are not satisfactory. Accordingly, there is a need to develop oligopeptides having high binding affinity to a BMP-specific receptor (e.g., BMPR-IA and BMPR-II) to show excellent initial osteointegration and osteogenesis abilities.